US2017114133A1PendingUtilityA1

Tem8 antibodies and methods of use

Assignee: BIOMED VALLEY DISCOVERIES INCPriority: Jun 9, 2014Filed: Jun 9, 2015Published: Apr 27, 2017

Est. expiryJun 9, 2034(~7.9 yrs left)· nominal 20-yr term from priority

C07K 2317/72A61K 38/05C07K 2317/732C07K 16/30C07K 2317/52C07K 2317/53A61K 31/5365C07K 2317/526C07K 2317/41C07K 14/70578A61P 35/00A61K 38/00C07K 2319/74C07K 2319/02C07K 2317/524G01N 2333/705C07K 2319/03C07K 2317/77C07K 16/28C07K 14/70521C07K 14/7051A61K 47/6851C07K 2317/567G01N 33/5759G01N 33/57492A61K 47/48569

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References

Claims

Abstract

The present invention provides, inter alia, isolated monoclonal and polyclonal anti-tumor endothelial marker 8 (TEM8) antibodies or antigen binding fragments thereof that (a) bind to TEM8 membrane antigen in its native form occurring on the surface of a tumor cell; (b) may be internalized by a tumor cell; (c) bind strongly to tumor cells but not or only minimally to cells which lack expression of TEM8; and (d) are characterized in that the mean fluorescence intensity (MFI) of the antibody or an antigen binding fragment thereof against a mammalian cell line expressing TEM8 is at least two times higher than the MFI against the mammalian cell line not expressing TEM8 at antigen saturation. Chimeric antigen receptors (CARs) including an antigen binding fragment of such antibodies, modified antibodies, compositions, pharmaceutical compositions, and kits including the antibodies according to the present invention, and methods of use are also provided.

Claims

exact text as granted — not AI-modified

1 . An isolated monoclonal antibody (mAb) or an antigen binding fragment thereof, which:
(a) binds to tumor endothelial marker 8 (TEM8) membrane antigen in its native form occurring on the surface of a tumor cell; (b) may be internalized by a tumor cell; (c) binds strongly to tumor cells but not or only minimally to cells which lack expression of TEM8; and (d) is characterized in that the mean fluorescence intensity (MFI) of the mAb or an antigen binding fragment thereof against a mammalian cell line expressing TEM8 is at least two times higher than the MFI of the mAb or an antigen binding fragment thereof against the mammalian cell line not expressing TEM8 at antigen saturation.

2 . The isolated mAb or an antigen binding fragment thereof according to claim 1 , wherein the mammalian cell line is a CHO cell line, and wherein the MFI of the mAb or an antigen binding fragment thereof against the CHO cell line expressing TEM8 is at least three times higher than the MFI of the mAb or an antigen binding fragment thereof against a CHO cell line not expressing TEM8 at antigen saturation.

3 . The isolated mAb or an antigen binding fragment thereof according to claim 2 , wherein the MFI of the mAb or an antigen binding fragment thereof against the CHO cell line expressing TEM8 is at least five times higher than the MFI of the mAb or an antigen binding fragment thereof against the CHO cell line not expressing TEM8 at antigen saturation.

4 . The isolated mAb or an antigen binding fragment thereof according to claim 2 , wherein the MFI of the mAb or an antigen binding fragment thereof against the CHO cell line expressing TEM8 is at least ten times higher than the MFI of the mAb or an antigen binding fragment thereof against the CHO cell line not expressing TEM8 at antigen saturation.

5 . The isolated mAb or an antigen binding fragment thereof according to claim 1 , which is selected from the group consisting of 1A2.B12, 1A2.D12, 1A2.E12, 1C2.A11, 1C2.B11, 1C2.C10, 1C2.E8, 3C5.A11, 3C5.B10, 6H6.C12, 7B2.A11, 7B2.B10, 7B7.B12, 8D3.D11, 8H2.B11, 8H2.C12, and antigen binding fragments thereof.

6 . The isolated mAb or an antigen binding fragment thereof according to claim 1 , which further comprises a human framework region.

7 . The isolated mAb or an antigen binding fragment thereof according to claim 1 , which is a humanized antibody, a chimeric antibody, or a recombinant antibody.

8 . The isolated mAb or an antigen binding fragment thereof according to claim 1 , wherein the antibody is an IgG.

9 . The isolated mAb or an antigen binding fragment thereof according to claim 1 , wherein the antigen binding fragment of the mAb is a Fv, a Fab, a F(ab′)2, a scFV or a scFV2 fragment.

10 . The isolated mAb or an antigen binding fragment thereof according to claim 1 , which is conjugated to a label or to an effector agent.

11 . The isolated mAb or an antigen binding fragment thereof according to claim 10 , wherein the label is selected from the group consisting of a fluorescent marker, an enzymatic marker, a heavy metal, a radioactive marker, and combinations thereof.

12 . The isolated mAb or an antigen binding fragment thereof according to claim 10 , wherein the effector agent is selected from the group consisting of a chemotherapeutic, a toxin, and combinations thereof.

13 . The isolated mAb or an antigen binding fragment thereof according to claim 10 , wherein the effector agent is a cell toxic substance selected from the group consisting of taxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etopside, tenopside, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxy antracin dione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glycocorticoids, procaine, tetracaine, lidokaine, propranolol, puromycin and combinations thereof.

14 . The isolated mAb or an antigen binding fragment thereof according to claim 10 , wherein the isolated mAb or antigen binding fragment thereof is conjugated to the effector agent or to the detectable marker by a linker.

15 . The isolated mAb or an antigen binding fragment thereof according to claim 14 , wherein the linker is a cleavable linker.

16 . The isolated mAb or an antigen binding fragment thereof according to claim 14 , wherein the linker is a cathepsin-cleavable linker.

17 . The isolated mAb or an antigen binding fragment thereof according to claim 14 , wherein the linker is a non-cleavable linker.

18 . An isolated mAb selected from the group consisting of those clones listed in Table 1A below and having the listed characteristics:

TABLE 1A

Clone
Clone
Clone

binding to
binding to
binding to

CHO-TEM8
HEK-TEM8
HEK

Clone
(MFI)
(MFI)
(MFI)
Heavy
Light

1A2.B12
1445
365
161
IgG2a
K

1A2.D12
1166
750
69
IgG1
K

1A2.E12
813
486
127
IgG1
K

1C2.A11
1527
593
74
IgG1
K

1C2.B11
1427
472
35
IgG1
K

1C2.C10
2605
603
55
IgG1
K

1C2.E8
858
449
165
IgG1
K

3C5.A11
1474
406
129
IgG2b
K

3C5.B10
1025
259
57
IgG2b
K

6H6.C12
767
257
105
IgG1
K

7B2.A11
1241
331
90
IgG2a
K

7B2.B10
1376
243
82
IgG2b
K

7B7.B12
1411
432
142
IgG2b
K

8D3.D11
172
223
43
IgG2b
K

8H2.B11
1055
150
50
IgG1
K

8H2.C12
2237
405
74
IgG1
K

19 . A chimeric antigen receptor (CAR) comprising:
(a) an antigen binding fragment of an antibody according to claim 1 ; and (b) a signaling domain of a T-cell receptor.

20 . The CAR according to claim 19 , wherein the signaling domain of the T-cell receptor is selected from the group consisting of: (i) human CD28, human 4-1 BB, and human CD3ζ intracellular T cell receptor signaling domains; (ii) human CD28 and human CD3ζ intracellular T cell receptor signaling domains; (iii) mouse CD28, mouse 4-1BB, and mouse CD3ζ intracellular T cell receptor signaling domains; and (iv) mouse CD28 and mouse CD3ζ intracellular signaling domains.

21 . A modified antibody that binds a TEM8 antigen, the modified antibody comprising a variant human IgG1 Fc region, wherein the variant human IgG1 Fc region comprises at least one amino acid modification relative to the human IgG1 Fc region of a parent antibody according to claim 18 that binds the TEM8 antigen, the amino acid modification(s) comprising amino acid modification(s) that alter the affinity or avidity of the variant Fc region for binding to an FcγR, such that the modified antibody exhibits, in an in vitro assay, enhanced effector function activity mediated by the FcγR binding in cells positive for the TEM8 antigen, and the parent antibody exhibits lower or non-detectable effector function activity in the cells using the in vitro assay, the amino acid modification(s) that alter the affinity or avidity of the variant Fc region for binding to an FcγR consisting of the modification of 1, 2, 3, 4 or 5 amino acid residues of the IgG1 Fc region of the parent antibody.

22 . A modified antibody that binds a TEM8 antigen, the modified antibody comprising a variant human IgG1 Fc region, wherein the variant human IgG1 Fc region comprises at least one amino acid modification relative to the human IgG1 Fc region of a parent antibody according to claim 18 that binds the TEM8 antigen, the amino acid modification(s) comprising amino acid modification(s) that alter the affinity or avidity of the variant Fc region for binding to an FcγR, such that the modified antibody exhibits enhanced effector function activity mediated by the FcγR binding in cells positive for the antigen and the parent antibody exhibits lower or non-detectable effector function activity; such that the modified antibody is therapeutically effective in a subject refractory to treatment with the parent antibody, the amino acid modification(s) that alter the affinity or avidity of the variant Fc region for binding to an FcγR consisting of the modification of 1, 2, 3, 4 or 5 amino acid residues of the IgG1 Fc region of the parent antibody.

23 . The modified antibody of claim 22 , wherein the modified antibody exhibits, in an in vitro assay, detectable effector function activity in cells derived from the subject, which cells are positive for the TEM8 antigen, and the parent antibody does not exhibit detectable functional activity in the cells using the in vitro assay.

24 . The modified antibody according to claim 21 , wherein the TEM8 antigen is expressed on the surface of an endothelial cell.

25 . The modified antibody according to claim 21 , wherein the amino acid modification(s) that alter the affinity or avidity of the variant Fc region for binding to an FcγR comprise(s) a substitution:
(i) at position 370 with glutamic acid, at position 396 with leucine and at position 270 with glutamic acid;
(ii) at position 419 with histidine, at position 396 with leucine and at position 270 with glutamic acid;
(iii) at position 240 with alanine, at position 396 with leucine and at position 270 with glutamic acid;
(iv) at position 255 with leucine, at position 396 with leucine and position 270 with glutamic acid;
(v) at position 255 with leucine, at position 396 with leucine, at position 270 with glutamic acid and at position 292 glycine; or
(vi) at position 255 with leucine, at position 396 with leucine, at position 270 with glutamic acid and at position 300 leucine.

26 . The modified antibody according to claim 21 , wherein at least one of the amino acid modification(s) that alter the affinity or avidity of the variant Fc region for binding to an FcγR is in a CH2 domain of the variant human IgG1 Fc region.

27 . The modified antibody according to claim 26 , wherein the amino acid modification(s) that alter the affinity or avidity of the variant Fc region for binding to an FcγR in the CH2 domain comprises a substitution at position 240, 243, 247, 255, 270, 292, or 300 with another amino acid at that position.

28 . The modified antibody according to claim 21 , wherein at least one of the amino acid modification(s) that alter the affinity or avidity of the variant Fc region for binding to an FcγR is in a CH3 domain of the variant human IgG1 Fc region.

29 . The modified antibody according to claim 28 , wherein the amino acid modification(s) that alter the affinity or avidity of the variant Fc region for binding to an FcγR in the CH3 domain comprises a substitution at position 370, 392, 396, 419, or 421 with another amino acid at that position.

30 . The modified antibody according to claim 21 , wherein the amino acid modification(s) that alter the affinity or avidity of the variant Fc region for binding to an FcγR comprises at least one amino acid modification in the CH2 domain and at least one amino acid modification in the CH3 domain of the Fc region.

31 . The modified antibody according to claim 21 , wherein the amino acid modification(s) that alter the affinity or avidity of the variant Fc region for binding to an FcγR is in the hinge region of the human IgG1 heavy chain.

32 . The modified antibody according to claim 31 comprising at least one amino acid modification that alters the affinity or avidity of the variant Fc region for binding to an FcγR in the hinge region of the human IgG1 heavy chain.

33 . The modified antibody according to claim 21 , which variant IgG1 Fc region specifically binds FcγRIIIA with a greater affinity than the parent antibody binds FcγRIIIA.

34 . The modified antibody according to claim 21 , which variant IgG1 Fc region specifically binds FcγRIIA with a greater affinity than the parent antibody binds FcγRIIA.

35 . The modified antibody according to claim 21 , which variant IgG1 Fc region specifically binds FcγRIIB with a lower affinity than the parent antibody binds FcγRIIB.

36 . The modified antibody according to claim 33 , which variant IgG1 Fc region specifically binds FcγRIIB with a lower affinity than the parent antibody binds FcγRIIB.

37 . The modified antibody according to claim 34 , which variant IgG1 Fc region specifically binds FcγRIIB with a lower affinity than the parent antibody binds FcγRIIB.

38 . The modified antibody according to claim 21 , which detectably binds endothelial cells positive for the TEM8 antigen, which antigen is expressed at a density of 200 to 1,000 molecules/cell on the cells.

39 . The modified antibody according to claim 21 wherein the effector function is antibody dependent cell-mediated cell cytotoxicity (ADCC).

40 . The modified antibody according to claim 21 wherein the effector function is phagocytosis, opsonization, cell binding, rosetting, complement dependent cell mediated cytotoxicity (CDC), or antibody dependent cell-mediated cell cytotoxicity (ADCC).

41 . An isolated mAb according to claim 18 , wherein the antibody is non-fucosylated or has reduced fucosylation in the Fc region compared to the parent monoclonal antibody.

42 . A modified antibody according to claim 21 , wherein the antibody is non-fucosylated or has reduced fucosylation in the Fc region compared to the parent monoclonal antibody.

43 . A composition comprising an effector agent or a detectable marker, which agent or marker is conjugated to a mAb or antigen binding fragment thereof, wherein the mAb or antigen binding fragment thereof:
(a) binds to tumor endothelial marker 8 membrane (TEM8) antigen in its native form occurring on the surface of a tumor cell; (b) may be internalized by a tumor cell; (c) binds strongly to tumor cells but not or only minimally to cells which lack expression of TEM8; and (d) is characterized in that the mean fluorescence intensity (MFI) of the mAb or an antigen binding fragment thereof against a mammalian cell line expressing TEM8 is at least two times higher than the MFI of the mAb or an antigen binding fragment thereof against the mammalian cell line not expressing TEM8 at antigen saturation.

44 . The composition according to claim 43 , wherein the mAb or antigen binding fragment thereof, comprises a human framework region.

45 . The composition according to claim 43 , wherein the antibody is an IgG.

46 . The composition according to claim 43 , which comprises the antigen binding fragment of the mAb.

47 . The composition according to claim 43 , wherein the antigen binding fragment is a Fv, a Fab, a F(ab′)2, a scFV or a scFV2 fragment.

48 . The composition according to claim 43 , wherein the effector agent is a chemotherapeutic agent.

49 . The composition according to claim 48 , wherein the chemotherapeutic agent is 5-fluorouracil or irinotecan.

50 . The composition according to claim 43 , wherein the effector agent is an anti-angiogenic agent.

51 . The composition according to claim 43 , wherein the effector agent is a toxin.

52 . The composition according to claim 51 , wherein the toxin is a maytansinoid toxin.

53 . The composition according to claim 52 , wherein the maytansinoid toxin is DM1.

54 . The composition according to claim 51 , wherein the toxin is an auristatin toxin.

55 . The composition according to claim 54 , wherein the auristatin toxin is Monomethyl Auristatin E (MMAE) or Monomethyl Auristatin F (MMAF).

56 . The composition according to claim 43 , wherein the detectable marker is selected from the group consisting of a fluorescent marker, an enzymatic marker, a heavy metal, a radioactive marker and combinations thereof.

57 . The composition according to claim 43 , wherein the isolated mAb or antigen binding fragment thereof is conjugated to the effector agent or the detectable marker by a linker.

58 . The composition according to claim 57 , wherein the linker is a cleavable linker.

59 . The composition according to claim 57 , wherein the linker is a cathepsin-cleavable linker.

60 . The composition according to claim 57 , wherein the linker is a non-cleavable linker.

61 . A pharmaceutical composition comprising an effective amount of the composition of claim 43 and a pharmaceutically acceptable carrier.

62 . A pharmaceutical composition comprising an isolated mAb or an antigen binding fragment thereof according to claim 1 .

63 . A pharmaceutical composition comprising an effective amount of a mAb according to claim 18 and a pharmaceutically acceptable carrier.

64 . A pharmaceutical composition comprising an effective amount of a CAR according to claim 19 and a pharmaceutically acceptable carrier.

65 . A pharmaceutical composition comprising the modified antibody of any claim 21 and a pharmaceutically acceptable carrier.

66 . A kit for treating or ameliorating the effects of a cancer in a subject comprising an isolated mAb or an antigen binding fragment thereof according to claim 1 packaged in combination with instructions for its use.

67 . A kit for treating or ameliorating the effects of a cancer in a subject, the kit comprising the isolated mAb according to claim 18 packaged in combination with instructions for its use.

68 . A kit for treating or ameliorating the effects of a cancer in a subject, the kit comprising the CAR according to claim 19 packaged in combination with instructions for its use.

69 . A kit for treating or ameliorating the effects of a cancer in a subject, the kit comprising the modified antibody according to claim 21 packaged in combination with instructions for its use.

70 . A kit for treating or ameliorating the effects of a cancer in a subject, the kit comprising the composition of claim 43 packaged in combination with instructions for its use.

71 . A kit for treating or ameliorating the effects of a cancer in a subject comprising a pharmaceutical composition according to claim 61 packaged in combination with instructions for its use.

72 . A kit for treating or ameliorating the effects of a cancer in a subject comprising a pharmaceutical composition according to claim 62 packaged in combination with instructions for its use.

73 . A kit for treating or ameliorating the effects of a cancer in a subject comprising a pharmaceutical composition according to claim 63 packaged in combination with instructions for its use.

74 . A kit for treating or ameliorating the effects of a cancer in a subject comprising a pharmaceutical composition according to claim 64 packaged in combination with instructions for its use.

75 . A kit for treating or ameliorating the effects of a cancer in a subject comprising a pharmaceutical composition according to claim 65 packaged in combination with instructions for its use.

76 . A kit for the detection of a tumor cell comprising an isolated mAb or an antigen binding fragment thereof according to claim 1 packaged in combination with instructions for its use.

77 . A kit for the detection of a tumor cell comprising the isolated mAb according to claim 18 packaged in combination with instructions for its use.

78 . A kit for the detection of pathological angiogenesis in a subject comprising an isolated mAb or an antigen binding fragment thereof according to claim 1 packaged in combination with instructions for its use.

79 . A kit for the detection of pathological angiogenesis in a subject comprising the isolated mAb according to claim 18 packaged in combination with instructions for its use.

80 . A method for identifying tumor cells comprising:
(a) contacting a cell to be identified with an isolated mAb or an antigen binding fragment thereof according to claim 1 ; and (b) identifying those cells to which the mAb or antigen binding fragment thereof specifically binds, wherein those cells bound to the mAb or antigen binding fragment thereof are tumor cells.

81 . The method according to claim 80 , wherein the tumor cell is an endothelial cell that expresses TEM8.

82 . The method according to claim 80 , which is carried out in vitro.

83 . The method according to claim 80 , which is carried out in vivo.

84 . The method according to claim 80 further comprising, prior to step (a), obtaining a sample from a subject suspected of having a cancer and carrying out steps (a) and (b) with the sample.

85 . The method according to claim 80 , wherein the sample is selected from the group consisting of blood, urine, spinal fluid, amniotic fluid, serum, plasma, gingival, cervicular fluid, lachrymal fluid, lymph, mammary gland secretions, mucus, saliva, semen, tears, vaginal secretions, and vitreous humor.

86 . A method for treating or ameliorating the effects of a disease in a subject comprising administering to a subject in need thereof an effective amount of the isolated mAb or an antigen binding fragment thereof according to claim 1 .

87 . The method according to claim 86 , wherein the disease is a cancer that expresses TEM8.

88 . A method for treating or ameliorating the effects of a disease in a subject comprising administering to a subject in need thereof an effective amount of the isolated mAb according to claim 18 .

89 . The method according to claim 88 , wherein the disease is a cancer that expresses TEM8.

90 . A method for treating or ameliorating the effects of a disease in a subject comprising administering to a subject in need thereof an effective amount of the CAR according to claim 19 .

91 . The method according to claim 90 , wherein the disease is a cancer that expresses TEM8.

92 . A method for treating or ameliorating the effects of a disease in a subject comprising administering to a subject in need thereof an effective amount of the modified antibody according to claim 21 .

93 . The method according to claim 92 , wherein the disease is a cancer that expresses TEM8.

94 . A method for treating or ameliorating the effects of a disease in a subject comprising administering to a subject in need thereof an effective amount of the composition according to claim 43 .

95 . The method according to claim 94 , wherein the disease is a cancer that expresses TEM8.

96 . A method for treating or ameliorating the effects of a disease in a subject comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition according to claim 61 .

97 . The method according to claim 96 , wherein the disease is a cancer that expresses TEM8.

98 . A method for treating or ameliorating the effects of a disease in a subject comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition according to claim 62 .

99 . The method according to claim 98 , wherein the disease is a cancer that expresses TEM8.

100 . A method for treating or ameliorating the effects of a disease in a subject comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition according to claim 63 .

101 . The method according to claim 100 , wherein the disease is a cancer that expresses TEM8.

102 . A method for treating or ameliorating the effects of a disease in a subject comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition according to claim 64 .

103 . The method according to claim 102 , wherein the disease is a cancer that expresses TEM8.

104 . A method for treating or ameliorating the effects of a disease in a subject comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition according to claim 65 .

105 . The method according to claim 104 , wherein the disease is a cancer that expresses TEM8.

106 . A method of modulating the binding of an anthrax protective antigen to a cell comprising: contacting the cell with an effective amount of an isolated mAb or an antigen binding fragment thereof according to claim 1 to modulate the binding of the anthrax protective antigen to the cell.

107 . The method according to claim 106 , wherein the contacting is carried out in vitro.

108 . The method according to claim 106 , wherein the contacting is carried out in vivo.

109 . A method of modulating the binding of an anthrax protective antigen to a cell comprising: contacting the cell with an effective amount of an isolated mAb or an antigen binding fragment thereof according to claim 18 to modulate the binding of the anthrax protective antigen to the cell.

110 . The method according to claim 109 , wherein the contacting is carried out in vitro.

111 . The method according to claim 109 , wherein the contacting is carried out in vivo.

112 . A polyclonal antibody which:
(a) binds to tumor endothelial marker 8 (TEM8) membrane antigen in its native form occurring on the surface of a tumor cell; (b) may be internalized by a tumor cell; (c) binds strongly to tumor cells but not or only minimally to cells which lack expression of TEM8; and (d) is characterized in that the mean fluorescence intensity (MFI) of the polyclonal antibody against a mammalian cell line expressing TEM8 is at least two times higher than the MFI of the polyclonal antibody against the mammalian cell line not expressing TEM8 at antigen saturation.

113 . A polyclonal antibody selected from the group consisting of those clones listed in Table 1B below and having the listed characteristics:

TABLE 1B

binding to
binding to
binding to

CHO-TEM8
HEK-TEM8
HEK

Name
(MFI)
(MFI)
(MFI)
Heavy
Light

3C5.E7
536
215
92
IgG2b/IgG1
K

6H6.B11
963
232
96
IgG1
K

7B2.D9
678
284
102
IgG2a
K

7B7.E9
852
324
96
IgG2a
K/λ

114 . A composition comprising an effector agent or a detectable marker, which agent or marker is conjugated to a polyclonal antibody, wherein the polyclonal antibody:
(a) binds to tumor endothelial marker 8 (TEM8) membrane antigen in its native form occurring on the surface of a tumor cell; (b) may be internalized by a tumor cell; (c) binds strongly to tumor cells but not or only minimally to cells which lack expression of TEM8; and (d) is characterized in that the mean fluorescence intensity (MFI) of the polyclonal antibody against a mammalian cell line expressing TEM8 is at least two times higher than the MFI of the polyclonal antibody against the mammalian cell line not expressing TEM8 at antigen saturation.

115 . A pharmaceutical composition comprising an effective amount of a polyclonal antibody according to claim 112 and a pharmaceutically acceptable carrier.

116 . A kit for treating or ameliorating the effects of a cancer in a subject comprising a polyclonal antibody according claim 112 packaged in combination with instructions for use.

117 . A kit for treating or ameliorating the effects of a cancer in a subject comprising a pharmaceutical composition according to claim 115 packaged in combination with instructions for use.

118 . A kit for the detection of a tumor cell comprising a polyclonal antibody according to claim 112 packaged in combination with instructions for use.

119 . A method for treating or ameliorating the effects of a disease in a subject comprising administering to a subject in need thereof an effective amount of a polyclonal antibody according claim 112 .

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